title: Activation of natural killer T cells by α-carba-GalCer (RCAI-56), a novel synthetic glycolipid ligand, suppresses murine collagen-induced arthritis.
abstract: Alpha-carba-GalCer (RCAI-56), a novel synthetic analogue of α-galactosylceramide (α-GalCer), stimulates invariant natural killer T (NK T) cells to produce interferon (IFN)-γ. IFN-γ exhibits immunoregulatory properties in autoimmune diseases by suppressing T helper (Th)-17 cell differentiation and inducing regulatory T cells and apoptosis of autoreactive T cells. Here, we investigated the protective effects of α-carba-GalCer on collagen-induced arthritis (CIA) in mice. First, we confirmed that α-carba-GalCer selectively induced IFN-γ in CIA-susceptible DBA/1 mice in vivo. Then, DBA/1 mice were immunized with bovine type II collagen (CII) and α-carba-GalCer. The incidence and clinical score of CIA were significantly lower in α-carba-GalCer-treated mice. Anti-IFN-γ antibodies abolished the beneficial effects of α-carba-GalCer, suggesting that α-carba-GalCer ameliorated CIA in an IFN-γ-dependent manner. Treatment with α-carba-GalCer reduced anti-CII antibody production [immunoglobulin (Ig)G and IgG2a] and CII-reactive interleukin (IL)-17 production by draining lymph node (DLN) cells, did not induce apoptosis or regulatory T cells, and significantly increased the ratio of the percentage of IFN-γ-producing T cells to IL-17-producing T cells (Th1/Th17 ratio). Moreover, the gene expression levels of IL-6 and IL-23p19, Th17-related cytokines, were reduced significantly in mice treated with α-carba-GalCer. In addition, we observed higher IFN-γ production by NK T cells in α-carba-GalCer-treated mice in the initial phase of CIA. These findings indicate that α-carba-GalCer polarizes the T cell response toward Th1 and suppresses Th17 differentiation or activation, suggesting that α-carba-GalCer, a novel NK T cell ligand, can potentially provide protection against Th17-mediated autoimmune arthritis by enhancing the Th1 response.
authors.affiliation: Division of Clinical Immunology, Doctoral Program in Clinical Sciences, University of Tsukuba, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Yoshiga
authors.forename: D
authors.initials: D
authors.lastname: Goto
authors.forename: S
authors.initials: S
authors.lastname: Segawa
authors.forename: M
authors.initials: M
authors.lastname: Horikoshi
authors.forename: T
authors.initials: T
authors.lastname: Hayashi
authors.forename: I
authors.initials: I
authors.lastname: Matsumoto
authors.forename: S
authors.initials: S
authors.lastname: Ito
authors.forename: M
authors.initials: M
authors.lastname: Taniguchi
authors.forename: T
authors.initials: T
authors.lastname: Sumida
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D002417:Cattle; D024043:Collagen Type II / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D005699:Galactosylceramides / Q000494:pharmacology / Q000627:therapeutic use*; D007155:Immunologic Factors / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D053759:Interleukin-23 / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D008024:Ligands; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D055611:Natural Killer T-Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000187:drug effects
chemical_list: D024043:Collagen Type II; D005699:Galactosylceramides; D007155:Immunologic Factors; D053759:Interleukin-23; D015850:Interleukin-6; D008024:Ligands; C558673:alpha-carba-galactosylceramide; D007371:Interferon-gamma